Pyrrolidonecarboxylic acid derivatives as anti-ulcer agents

ABSTRACT

A series of novel N-(p-benzamido)-2-pyrrolidone-4-carboxylic acid compounds have been prepared by condensing the corresponding p-aminobenzamides with itaconic acid. These pyrrolidone compounds are useful in therapy as anti-ulcer agents. N-[N&#39;-(n-Decyl)-4&#39;-benzamido]-2-pyrrolidone-4-carboxylic acid represents a preferred embodiment.

BACKGROUND OF THE INVENTION

This invention relates to new and useful N-substitutedpyrrolidonecarboxylic acid compounds of principal interest to those inthe field of chemotherapy. More particularly, it is concerned withcertain novel N-(p-benzamido)-2-pyrrolidone-4-carboxylic acid compounds,which are of especial value in view of their unique anti-ulcerproperties.

In the past, various attempts have been made by numerous investigatorsin the field of organic medicinal chemistry to obtain new and usefulanti-ulcer agents. For the most part, these efforts have involved thesynthesis and testing of various new and heretofore unavailable organiccompounds, particularly in the area of organic heterocyclic bases. Forinstance, C. A. Lipinski in U.S. Pat. No. 3,862,190 discloses various4-amino-5-phenoxypyrimidine compounds useful for these purposes.However, in the search for still new and better or more improvedanti-ulcer agents, little is known about the effect of acidic functionalgroups on compounds of this type and particularly, a carboxylic acidgroup attached to a heterocyclic ring moiety.

SUMMARY OF THE INVENTION

In accordance with the present invention, it has now been ratherunexpectedly found that certain novel N-substitutedpyrrolidonecarboxylic acid compounds are extremely useful when employedin therapy as anti-ulcer agents. More specifically, the novel compoundsof this invention are all selected from the group consisting ofN-(p-benzamido)-2-pyrrolidone-4-carboxylic acids of the formula:##STR1## and the lower alkyl esters and unsubstituted amide derivativesthereof, and the base salts of said acids with pharmacologicallyacceptable cations, wherein R is a member selected from the groupconsisting of alkyl having from seven to eighteen carbon atoms arrangedin a straight chain, benzyl, β-phenylethyl and 2-pyridyl. These novelcompounds all possess anti-ulcer activity to a significantly high degreeand are therefore useful in the treatment of peptic ulcers.

Of especial interest in this connection are such typical and preferredmember compounds of the invention asN-[N'-(n-octyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid,N-[N'-(n-nonyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid,N-[N'-(n-decyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid,N-[N'-(n-undecyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid,N-[N'-(n-dodecyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid andN-[N'-(2-pyridyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid,respectively. These particular compounds are all highly potent asregards their anti-ulcer activity.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the process employed for preparing the novelcompounds of this invention, an appropriatep-amino-N-(substituted)benzamide of the formula: ##STR2## wherein R isdefined as aforesaid, is condensed with itaconic acid to form thedesired N-(p-benzamido)-2-pyrrolidone-4-carboxylic acid final product ofthe structural formula previously indicated. This particular reaction isnormally conducted in the absence of a solvent by fusing the tworeactants together at a temperature that is at least about equal to theboiling point of water, whereby the resultant water of reaction issubstantially removed from the reaction mixture as quickly as it isformed. The reaction may also be conducted in the presence of a solventsuch as benzene, toluene, n-hexane and methyl isobutyl ketone, etc. Apreferred temperature for the reaction would be one that is normally inthe range of from about 100° to about 140° C. for the present purposesat hand, i.e., until all the water of reaction has been substantiallyremoved from the reaction mixture and this will usually require a periodof at least about an hour. In general, substantially equimolarproportions of reactants are employed, although the ratio can varyanywhere from about 0.5 to about 2.0 moles of itaconic acid per mole ofamine without causing unwanted side reactions to occur to anysignificant degree. Upon completion of the reaction, the desired productis easily isolated in a conventional manner, e.g., by first cooling thereaction mixture to room temperature and then dissolving same in diluteaqueous alkali, followed by filtration and subsequent acidification ofthe resulting filtrate to afford the particularN-(p-benzamido)-2-pyrrolidone-4-carboxylic acid in the form of areadily-recoverable precipitate.

The lower alkyl esters of the N-(p-benzamido)-2-pyrrolidone-4-carboxylicacids of this invention are generally prepared by condensation of theacid with the appropriate alcohol in the presence of an acid catalyst inaccordance with conventional organic procedure. The unsubstituted amidederivatives, on the other hand, are readily prepared by using standardprocedures, for example, by treating the corresponding acid chloridewith ammonia under basic conditions and thereafter isolating the amidefinal product in the usual manner.

The starting materials required for preparing the novelN-(p-benzamido)-2-pyrrolidone-4-carboxylic acid compounds of thisinvention are either readily available commercially, like itaconic acid,or else they can easily be synthesized by those skilled in the artstarting from common chemical reagents and using conventional methods oforganic synthesis. For instance, the p-amino-N-alkylbenzamides are allreadily prepared by reacting p-nitro-benzoyl chloride with theappropriate alkyl amine (RNH₂) and thereafter subjecting the resultingp-nitro-N-alkylbenzamide intermediate to catalytic hydrogenation inaccordance with the general procedure of H. Wenker, as described in theJournal of the American Chemical Society, Vol. 60, p. 1081 (1938).

The chemical bases which are used as reagents in this invention toprepare the aforementioned pharmaceutically acceptable base salts arethose which form non-toxic salts with the various herein describedN-(p-benzamido)-2-pyrrolidone-4-carboxylic acid, such asN-[N'-(n-decyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid, forexample. These particular non-toxic base salts are of such a nature thattheir cations are said to be essentially non-toxic in character over thewide range of dosage administered. Examples of such cations includethose of sodium, potassium, calcium and magnesium, etc. These salts caneasily be prepared by simply treating the aforementionedN-(p-benzamido)-2-pyrrolidone-4-carboxylic acids with an aqueoussolution of the desired pharmacologically acceptable cation, and thenevaporating the resulting solution to dryness while preferably beingplaced under reduced pressure. Alternatively, they may also be preparedby mixing lower alkanolic solutions of the said acidic compounds and thedesired alkali metal alkoxide together, and then evaporating theresulting solution to dryness in the same manner as before. In eithercase, stoichiometric quantities of reagents must be employed in order toensure completeness of reaction and maximum production of yields withrespect to the desired final product.

As previously indicated, the N-(p-benzamido)-2-pyrrolidone-4-carboxylicacid compounds of this invention are all readily adapted to therapeuticuse as anti-ulcer agents, especially in view of their ability to controlpeptic ulcer formation in stressed subjects to a statisticallysignificant degree. For instance,N-[N'-(n-decyl)-4-benzamido]-2-pyrrolidone-4-carboxylic acid, a typicaland preferred agent of the present invention, has been found toconsistently control (i.e., inhibit) the formation of peptic ulcers instressed rats to a significantly high degree when given by theintraperitoneal route of administration at dose levels ranging from 10mg./kg. to 32 mg./kg., respectively, without showing any substantialsigns of toxic side effects. The other compounds of this invention alsocause similar results. Furthermore, all the herein described compoundsof this invention can be administered orally, for the present purposesat hand, without causing any significant untoward pharmacological sidereactions to occur in the subject to whom they are so administered. Ingeneral, those compounds are oridnarily administered at dosage levelsranging from about 1.0 mg. to about 25 mg. per kg. of body weight perday, although variations will necessarily occur depending upon thecondition and individual response of the subject being treated and theparticular type of pharmaceutical formulation chosen.

In connection with the use of theN-(p-benzamido)-2-pyrrolidone-4-carboxylic acid compounds of thisinvention for the treatment of subjects afflicted with peptic ulcers, itis to be noted that they may be administered either alone or incombination with pharmaceutically acceptable carriers and that suchadministration can be carried out in both single and multiple dosages.More particular, the novel compounds of this invention can beadministered in a wide variety of different dosage forms, i.e., they maybe combined with various pharmaceutically acceptable inert carriers inthe form of tablets, capsules, lozenges, troches, hard candies, powders,aqueous suspensions, elixirs, syrups and the like. Such carriers includesolid diluents or fillers, sterile aqueous media and various non-toxicorganic solvents, etc. Moreover, such standard pharmaceuticalcompositions can be suitably sweetened and/or flavored by means ofvarious agents of the type commonly employed for just such a purpose. Ingeneral, the therapeutically-effective compounds of this invention arepresent in such dosage forms at concentration levels ranging from about0.5% to about 90% by weight of the total composition, i.e., in amountswhich are sufficient to provide the desired unit dosage.

For purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and dicalciumphosphate may be employed along with various disintegrants such asstarch and preferably potato or tapioca starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, gelatin and acacia. Additionally, lubricatingagents such as magnesium stearate, sodium lauryl sulfate and talc areoften very useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard-filledgelatin capsules; preferred materials in this connection would alsoinclude lactose or milk sugar as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the essential active ingredient thereinmay be combined with various sweetening or flavoring agents, coloringmatter or dyes and, if so desired, emulsifying and/or suspending agentsas well, together with such diluents as water, ethanol, propyleneglycol, glycerin and various like combinations thereof.

The activity of the compounds of the present invention, as anti-ulceragents, is determined by their ability to inhibit ulcer formation incold-restraint stressed rats according to the procedure described by C.A. Lipinski in U.S. Pat. No. 3,862,190. The latter method essentiallycompares the median number of gastric erosions recorded in the controlgroup with the median number of gastric erosions recorded in thedrug-treated group and from this, the percent reduction in the totalnumber of lesions can be readily calculated and reported as antiulceractivity per se. In this way, theN-(p-benzamido)-2-pyrrolidone-4-carboxylic acid compounds of thisinvention are shown to markedly control peptic ulcer formation innon-fasted rats when administered to them intraperitoneally at doselevels as low as 10 mg./kg. for the present purposes at hand.

Preparation A

To a stirred solution consisting of 15.73 g. (0.10 mole) of n-decylaminedissolved in 200 ml. of chloroform at room temperature (˜25° C), therewere added 18.5 g. (0.10 mole of p-nitrobenzoyl chloride in the form ofa solid material divided into separate small portions. Upon completionof this step, 250 ml. of 5% aqueous sodium hydroxide solution wasrapidly added thereto and the resulting two-phase reaction mixture wasthen stirred overnight (˜16 hrs.) at room temperature and finallyallowed to separate. The aqueous phase was next washed once with 200 ml.of chloroform and the chloroform washing added to the organic phase,while the combined organic solution was thereafter washed once with 300ml. of a saturated aqueous sodium chloride solution and finally driedover anhydrous magnesium sulfate. After removal of the drying agent bymeans of suction filtration and the chloroform solvent by means ofevaporation under reduced pressure, there was obtained a crude solidresidue which subsequently gave 20.82 g. (95%) of purep-nitro-N-(n-decyl)benzamide (m.p. 88° -90° C.) on recrystallizationfrom a minimum amount of chloroform and methanol.

Preparation B

The procedure described in Preparation A was repeated to prepare thefollowing p-nitro-N-alkylbenzamides, using an equivalent amount in molesof the appropriate monoalkylamine compound as the reagent in eachinstance:

p-nitro-N-(n-octyl)benzamide, m.p. 82°-84° C.

p-nitro-N-(n-nonyl)benzamide, m.p. 79°-81° C.

p-nitro-N-(n-undecyl)benzamide, m.p. 88°-89° C.

p-nitro-N-(n-dodecyl)benzamide, m.p. 93°-94° C.

p-nitro-N-(n-tridecyl)benzamide, m.p. 85°-86° C.

p-nitro-N-(n-pentadecyl)benzamide, m.p. 95°-96° C.

p-nitro-N-(n-hexadecyl)benzamide, m.p. 96°-99° C.

Preparation C

The procedure described in Preparation A is repeated except thatn-octadecylamino is the reagent of choice employed in lieu ofn-decylamine and p-nitro-N-(n-octadecyl)benzamide is the correspondingfinal product thus obtained.

In like manner, the use of n-heptylamine as reagent in this reactionaffords p-nitro-N-(n-heptyl)benzamide as the corresponding final productwhich is obtained.

Preparation D

The procedure described in Preparation A is repeated except thatbenzylamine is the reagent of choice employed in lieu of n-decylamineand p-nitro-N-benzylbenzamide is the corresponding final product thusobtained.

In like manner, the use of β-phenylethylamine as reagent in thisreaction affords p-nitro-N-(β-phenylethyl)benzamide as the correspondingfinal product which is obtained.

Preparation E

A slurry of 29.00 g. (0.095 mole) of p-nitro-N-(n-decyl)benzamide in 200ml. of methanol contained in a Parr shaker bottle was warmed slightly todissolve all the benzamide. Adams platinum oxide catalyst (0.1 g.) wasthen added and the mixture placed on a Parr hydrogen reduction apparatusand shaken until no further hydrogen uptake could be detected (27.0 lb.of hydrogen were adsorbed over a period of 0.67 hrs.). The resultantslurry was next removed from the reaction vessel and subsequentlydissolved in 250 ml. of hot methanol, followed by filtration throughkieselguhr (infusorial earth) to remove the catalyst and a small amountof unidentified material that was insoluble in the hot methanol. Thealcoholic filtrate was then concentrated in vacuo and there wasultimately obtained a crude solid material which after recrystallizationfrom a minimum amount of methanol gave 22.0 g. (82%) of purep-amino-N-(n-decyl)benzamide, m.p. 114°-117° C.

Anal. Calcd. for C₁₇ H₂₈ N₂ O: C, 73.76; H, 10.21; N, 10.14. Found: C,74.03; H, 9.94; N, 10.27.

Preparation F

The procedure described in Preparation E was used to prepare thefollowing p-amino-N-alkylbenzamides, starting from the correspondingp-nitro-N-alkylbenzamide compound of Preparation B in each instance:

p-amino-N-(n-octyl)benzamide, m.p. 118°-120° C.

p-amino-N-(n-nonyl)benzamide, m.p. 111°-114° C.

p-amino-N-(n-undecyl)benzamide, m.p. 115°-117° C.

p-amino-N-(n-dodecyl)benzamide, m.p. 121°-122° C.

p-amino-N-(n-tridecyl)benzamide, m.p. 120°-121° C.

p-amino-N-(n-pentadecyl)benzamide, m.p. 117°-119° C.

p-amino-N-(n-hexadecyl)benzamide, m.p. 117°-120° C.

Preparation G

The procedure described in Preparation E is repeated except thatp-nitro-N-(n-octadecyl)benzamide is the starting material employed inplace of p-nitro-N-(n-decyl)benzamide andp-amino-N-(n-octadecyl)benzamide is the corresponding final product thusobtained.

In like manner, when p-nitro-(n-heptyl)benzamide is the startingmaterial employed in this reaction, the corresponding final productobtained is p-amino-N-(n-heptyl)benzamide.

Preparation H

The procedure described in Preparation E is repeated except thatp-nitro-N-benzylbenzamide is the starting material employed in place ofp-nitro-N-(n-decyl)benzamide and p-amino-N-benzylbenzamide is thecorresponding final product thus obtained.

In like manner, when p-nitro-N-(β-phenylethyl)benzamide is the startingmaterial employed in this reaction, the corresponding final productobtained is p-amino-N-(β-phenylethyl)benzamide.

EXAMPLE I

An intimate mixture of 22.0 g. (0.795 mole) ofp-amino-N-(n-decyl)benzamide and 10.34 g. (0.0795 mole) of itaconic acidwas prepared by combining said materials together in a suitableround-bottomed flask with the aid of a magnetic stirring apparatus. Themixture was then heated via an oil bath to a temperature of ca. 130° C.,while being maintained in a nitrogen atmosphere with continued stirring.At this point, the contents of the flask had completely turned to aliquid. After maintaining the bath temperature at 135° C. for a periodof 0.6 hours, the material started to solidify again and was completelysolid after an additional one-half hour at this same temperature. Thesample was then cooled to room temperature (˜25° C.) and dissolved in250 ml. of cold 0.5 N aqueous sodium hydroxide solution, followed byfiltration to remove any insoluble material present. The resultingfiltrate was then adjusted to pH 3.0 with 6 N hydrochloric acid, whilebeing maintained at 0° C. throughout this step by means of immersion inan ice bath. The precipitate which soon formed was filtered andthereafter washed with cold water and air-dried. Recrystallization ofthe crude material from absolute ethanol then gave 20.18 g. (67%) ofpure N-[N'-(n-decyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid, m.p.174°-177° C.

Anal. Calcd. for C₂₂ H₃₂ N₂ O₄ : C, 68.01; H, 8.30; N, 7.21. Found: C,68.14; H, 8.46; N, 7.40.

EXAMPLE II

The procedure described in Example I was repeated except thatp-amino-N-(n-octyl)benzamide was the starting material employed in placeof p-amino-N-(n-decyl)benzamide, using the same molar proportions asbefore. In this particular case, the corresponding final productobtained was N-[N'-(n-octyl)-4'-benzamido]-2-pyrrolidone-4-carboxylicacid, m.p. 175°-177° C.

Anal. Calcd. for C₂₀ H₂₈ N₂ O₄ : C, 68.35; H, 7.74; N, 7.97. Found: C,68.09; H, 7.88; N, 8.51.

EXAMPLE III

The procedure described in Example I was repeated except thatp-amino-N-(n-nonyl)benzamide was the starting material employed in placeof p-amino-N-(n-decyl)benzamide, using the same molar proportions asbefore. In this particular case, the corresponding final productobtained was N-[N'-(nonyl)-4'benzamido]-2-pyrrolidone-4-carboxylic acid,m.p. 175°-178° C.

Anal. Calcd. for C₂₁ H₃₀ N₂ O₄ : C, 67.35; H, 8.08; N, 7.48. Found: C,67.46; H, 8.00; N, 7.45.

EXAMPLE IV

The procedure described in Example I was repeated except thatp-amino-N-(n-undecyl)benzamide was the starting material employed inplace of p-amino-N-(n-decyl)benzamide, using the same molar proportionsas before. In this particular case, the corresponding final productobtained was N-[N'-(n-undecyl)-4'-benzamido]-2-pyrrolidone-4-carboxylicacid, m.p. 178°-180° C.

Anal. Calcd. for C₂₃ H₃₄ N₂ O₄ : C, 68.63; H, 8.51; N, 6.96. Found: C,68.87; H, 8.47; N, 7.02.

EXAMPLE V

The procedure described in Example I was repeated except thatp-amino-N-(n-dodecyl)benzamide was the starting material employed inplace of p-amino-N-(n-decyl)benzamide, using the same molar proportionsas before. In this particular case, the corresponding final productobtained was N[N'-(n-dodecyl)-4'-benzamido]-2-pyrrolidone-4-carboxylicacid, m.p. 177°-183° C.

Anal. Calcd. for C₂₄ H₃₆ N₂ O₄ : C, 69.20; H, 8.71; N, 6.73. Found: C,69.57; H, 8.65; N, 6.75.

EXAMPLE VI

The procedure described in Example I was repeated except thatp-amino-N-(n-tridecyl)benzamide was the starting material employed inplace of p-amino-N-(n-decyl)benzamide, using the same molar proportionsas before. In this particular case, the corresponding final productobtained was N-[N'-(n-tridecyl)-4'-benzamido]-2-pyrrolidone-4-carboxylicacid, m.p. 179°-181° C.

Anal. Calcd. for C₂₅ H₃₈ N₂ O₄ : C, 69.73; H, 8.90; N, 6.41. Found: C,70.50; H, 9.08; N, 6.41.

EXAMPLE VII

The procedure described in Example I was repeated except thatp-amino-N-(n-pentadecyl)benzamide was the starting material employed inplace of p-amino-N-(n-decyl)benzamide, using the same molar proportionsas before. In this particular case, the corresponding final productobtained wasN-[N'-(n-pentadecyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid, m.p.218°-220° C.

Anal. Calcd. for C₂₇ H₄₂ N₂ O₄ : C, 70.71; H, 9.23; N, 6.11. Found: C,70.86; H, 9.32; N, 6.06.

EXAMPLE VIII

The procedure described in Example I was repeated except thatp-amino-N-(n-hexadecyl)benzamide was the starting material employed inplace of p-amino-N-(n-decyl)benzamide, using the same molar proportionsas before. In this particular case, the corresponding final productobtained wasN-[N'-(n-hexadecyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid, m.p.160°-163° C.

Anal. Calcd. for C₂₈ H₄₄ N₂ O₄ : C, 71.15; H, 9.38; N, 5.93. Found: C,70.90; H, 9.24; N, 5.85.

EXAMPLE IX

The procedure described in Example I was repeated except thatp-amino-N-(2-pyridyl)benzamide [R. B. Moffett et al., Journal ofMedicinal Chemistry, Vol. 14. No. 10, p. 963 (1971)] was the startingmaterial employed in place of p-amino-N-(n-decyl)benzamide, using thesame molar proportions as before. In this particular case, thecorresponding final product obtained wasN-[N'-(2-pyridyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid, m.p.282.5°-282.5° C.

Anal. Calcd. for C₁₇ H₁₅ N₃ O₄ : C, 62.76: H, 4.65; N, 12.92. Found: C,62.48; H, 4.84; N, 12.68.

EXAMPLE X

The procedure described in Example I is repeated except thatp-amino-N-(3-pyridyl)benzamide is the starting material employed inplace of p-amino-N-(n-decyl)benzamide, using the same molar proportionsas before. In this particular case, the corresponding final productobtained is N-[N'-(3-pyridyl)-4'-benzamido]-2-pyrrolidone-4-carboxylicacid.

EXAMPLE XI

The procedure described in Example I is repeated except thatp-amino-N-(4-pyridyl)benzamide is the starting material employed inplace of p-amino-N-(n-decyl)benzamide, using the same molar proportionsas before. In this particular case, the corresponding final productobtained is N-[N'-(4-pyridyl)-4'-benzamido]-2-pyrrolidone-4-carboxylicacid.

EXAMPLE XII

The procedure described in Example I is repeated except thatp-amino-N-(n-octadecyl)benzamide is the starting material employed inplace of p-amino-N-(n-decyl)benzamide, using the same molar proportionsas before. In this particular case, the corresponding final productobtained is N-[N'-(n-octadecyl)-4'-benzamido]-2-pyrrolidone-4-carboxylicacid.

EXAMPLE XIII

The procedure described in Example I is repeated except thatp-amino-N-(n-heptyl)benzamide is the starting material employed in placeof p-amino-N-(n-decyl)benzamide, using the same molar proportions asbefore. In this particular case, the corresponding final productobtained is N-[N'-(n-heptyl)-4'-benzamido]-2-pyrrolidone-4-carboxylicacid.

EXAMPLE XIV

The procedure described in Example I is repeated except thatp-amino-N-benzylbenzamide is the starting material employed in place ofp-amino-N-(n-decyl)benzamide, using the same molar proportions asbefore. In this particular case, the corresponding final productobtained is N-(N'-benzyl-4'-benzamido)-2-pyrrolidone-4-carboxylic acid.

EXAMPLE XV

The procedure described in Example I is repeated except thatp-amino-N-(β-phenylethyl)benzamide is the starting material employed inplace of p-amino-N-(n-decyl)benzamide, using the same molar proportionsas before. In this particular case, the corresponding final productobtained isN-[N'-(β-phenylethyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid.

EXAMPLE XVI

A solution consisting of 3.88 g. (0.01 mole) ofN-[N'-(n-decyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid dissolvedin 100 ml. of ethanol is saturated with dry hydrogen chloride gas, andthe resultant mixture is then refluxed for a period of approximatelyfour hours. Upon completion of this step, the solvent is removed bymeans of evaporation under reduced pressure and the residue subsequentlymade alkaline by the addition thereto of a saturated aqueous sodiumbicarbonate solution. The resulting solution is then extracted withdiethyl ether, and the combined ethereal extracts are subsequently driedover anhydrous sodium sulfate and filtered. After removal of the dryingagent by means of filtration and the solvent in the usual manner, thereis obtained crude ester product in the form of a solid crystallineresidue. Recrystallization of the latter material from ethanol-waterthen affords the pure ethyl ester ofN-[N'-(n-decyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid insubstantial yield.

EXAMPLE XVII

The procedure described in Example XVI is repeated except that methanolis the reagent employed instead of ethanol and methylN-[N'-(n-decyl)-4'-benzamido]-2-pyrrolidone-4-carboxylate is thecorresponding final product thus obtained.

In like manner, the n-propyl, isopropyl, n-butyl, isobutyl, n-amyl,isoamyl and n-hexyl esters ofN-[N'-(n-decyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid are alsosimilarly prepared by merely employing the appropriate alcohol in placeof ethanol in each particular case.

EXAMPLE XVIII

The procedure described in Example XVI is repeated except thatN-[N'-(2-pyridyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid is thestarting material employed in place ofN-[N'-(n-decyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid for thepresent purposes at hand. In this particular case, the correspondingfinal product thus obtained is the ethyl ester ofN-[N'-(2-pyridyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid.

In like manner, the methyl, n-propyl, isopropyl, n-butyl, isobutyl,n-amyl, isoamyl and n-hexyl esters ofN-[N'-(2-pyridyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic are alsosimilarly prepared, as are the corresponding lower alkyl esters of theother N-(p-benzamido)-2-pyrrolidone-4-carboxylic acids of this inventionwhich are reported in Examples II-VIII and X-XV, respectively.

EXAMPLE XIX

A mixture of 1.94 g. (0.005 mole) ofN-[N'-(n-decyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid and 10 ml.of thionyl chloride dissolved in 300 ml. of chloroform is refluxed for aperiod of 2.5-3.9 hours. After cooling to room temperature (˜25° C.),the reaction mixture is slowly poured into a solution consisting of 4.5g. of sodium hydroxide dissolved in 100 ml. of ammonium hydroxide. Theresulting chloroform layer is then separated and subsequently evaporatedto near dryness while under reduced pressure to give a residual solid.Recrystallization of the latter material from ethanol-water then yieldspure N-[N'-(n-decyl)-4'-benzamido]-2-pyrrolidone-4-carboxamide in finecrystalline form.

EXAMPLE XX

The procedure described in Example XIX is repeated except thatN-[N'-(2-pyridyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid is thestarting material employed in place ofN-[N'-(n-decyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid for thepresent purposes at hand. In this particular case, the correspondingfinal product thus obtained isN-[N'-(2-pyridyl)-4'-benzamido]-2-pyrrolidone-4-carboxamide.

In like manner, the unsubstituted amides of the otherN-(p-benzamido)-2-pyrrolidone-4-carboxylic acids of this invention arealso similarly prepared by merely employing the appropriate acidstarting material (taken from Examples II-VIII and X-XV, respectively),in each particular case.

EXAMPLE XXI

The sodium salt ofN-[N'-(n-decyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid isprepared by dissolving said compound in water containing an equivalentamount in moles of sodium hydroxide and then freeze-drying the mixture.In this way, the desired alkali metal salt of the acid is obtained inthe form of an amorphous powder which is freely soluble in water.

In like manner, the potassium and lithium salts are also similarlyprepared, as are the alkali metal salts of all the otherN-(p-benzamido)-2-pyrrolidone-4-carboxylic acids of this invention whichare reported as Examples II-XV, respectively.

EXAMPLE XXII

The calcium salt ofN-[N'-(n-decyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid isprepared by dissolving said compound in water containing an equivalentamount of moles of calcium hydroxide and then freeze-drying the mixture.The corresponding magnesium salt is also prepared in like manner, as areall the other alkaline-earth metal salts not only of this particularcompound, but also of those acids previously described in ExamplesII-XV, respectively.

EXAMPLE XXIII

A dry solid pharmaceutical composition is prepared by blending thefollowing materials together in the proportions by weight specifiedbelow:

    ______________________________________                                        N-[N'-(n-Decyl)-4'-benzamido]-2-pyrrolidone-4-                                 carboxylic acid            50                                                Sodiumm citrate             25                                                Alginic acid                10                                                Polyvinylpyrrolidone        10                                                Magnesium stearate           5                                                ______________________________________                                    

After the dried composition is thoroughly blended, tablets are punchedfrom the resulting mixture, each table being of such size that itcontains 200 mg. of the active ingredient. Other tablets are alsoprepared in a similar fashion containing 25, 50 and 100 mg. of theactive ingredient, respectively, by merely using the appropriate amountof the N-(p-benzamido)-2-pyrrolidone-4-carboxylic acid in each case.

EXAMPLE XXIV

A dry solid pharmaceutical composition is prepared by combining thefollowing materials together in the proportions by weight indicatedbelow:

    ______________________________________                                        N-[N'-(2-Pyridyl)-4'-benzamido]-2-pyrrolidone-4-                               carboxylic acid             50                                               Calcium carbonate            20                                               Polyethylene glycol, average molecular weight 4000                                                         30                                               ______________________________________                                    

The dried solid mixture so prepared is then thoroughly agitated so as toobtain a powdered product that is completely uniform in every respect.Soft elastic and hard-filled gelatin capsules containing thispharmaceutical composition are then prepared, employing a sufficientquantity of material in each instance so as to provide each capsule with250 mg. of the active ingredient.

EXAMPLE XXV

The N-(p-benzamido)-2-pyrrolidone-4-carboxylic acids of Examples I-IXwere tested for antiulcer activity in groups of non-fasted female ratsof the Charles River C-D strain, each rat weighing approximately 70-140g. The rats were administered the test compound intraperitoneally (thecompound was dissolved in saline solution containing 1%carboxymethylcellulose and 0.1% polysorbate 80) at dose levels of 32mg./kg. and 10 mg./kg., respectively, three hours prior to being lightlyanesthetized with diethyl ether and then taped in the supine position toindividual sheets of acrylic plastic. Animals which received no testcompound (carrier only) served as the control. Upon recovery from theanesthesia, all the restrained animals were positioned horizontally in arefrigerator at 10°-12° C. for a period of three hours and thereaftersacrified by cervical dislocation. The abdomen of each rat that had beensubjected to the aforesaid cold-restraint stress was then opened, thepylorus clamped and the stomach inflated with saline solution via anoral tube. Upon completion of this step, the esophagus was then clampedand the stomach thereafter excised for examination purposes. This wasfurther facilitated by placing said organ in a 0.4% formaldehydesolution for approximately 30 seconds to harden the outer layers. Eachstomach was then cut open along the greater curvature and the glandularportion examined for damage. The number of gastric erosions, theirseverity, plus the color of the stomach, all served as items to berecorded. The Mann-Whitney-Wilcoxon rank sum test was then used tocompare the median number of gastric erosions in the control group withthe median number of said erosions in each drug-treated group in orderto determine if they are statistically different [E.g., see Dixon etal., "Introduction to Statistical Analysis," Third Edition, McGraw-HillBook Company, New York, N.Y., pp. 344- 347 (1969)]. On this basis, thepresent reduction in the total number of lesions (% R.T.L.) wascalculated and reported as such (i.e., as antiulcer activity) for thevarious compounds listed in the table below:

    ______________________________________                                                       Antiulcer Activity (% R.T.L.)                                   Compound        10 mg./kg.  32 mg./kg.                                       ______________________________________                                        Product of Example I                                                                           60          80                                               Product of Example II                                                                          55          25                                               Product of Example III                                                                         91          85                                               Product of Example IV                                                                          34          68                                               Product of Example V                                                                           65          46                                               Product of Example VI                                                                          34          62                                               Product of Example VII                                                                         --          43                                               Product of Example VIII                                                                        63          56                                               Product of Example IX                                                                          69          32                                               ______________________________________                                    

What is claimed is:
 1. A method for combatting peptic ulcers in thetreatment of a subject afflicted with said condition, which comprisesadministering to said subject a therapeutically-effective amount of acompound selected from the group consisting of anN-(p-benzamido)-2-pyrrolidone-4-carboxylic acid of the formula: ##STR3##a lower alkyl ester or the unsubstituted amide derivative thereof, and abase salt of said acid with a pharmacologically acceptable cation,wherein R is a member selected from the group consisting of alkyl havingfrom seven to eighteen carbon atoms arranged in a straight chain, benzyland β-phenylethyl.
 2. The method as claimed in claim 1 wherein thecompound administered isN-[N'-(n-octyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid.
 3. Themethod as claimed in claim 1 wherein the compound administered isN-[N'-(n-nonyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid.
 4. Themethod as claimed in claim 1 wherein the compound administered isN-[N'-(n-decyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid.
 5. Themethod as claimed in claim 1 wherein the compound administered isN-[N'-(n-undecyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid.
 6. Themethod as claimed in claim 1 wherein the compound administered isN-[N'-(n-dodecyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid.